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The present invention relates generally to smoking cessation methods and, more particularly, to a method for determining biological variations among individuals in a smoking cessation program so that a therapy regimen can be adjusted appropriately for each individual.
In the decades since the Surgeon General""s report associating smoking with serious diseases and increased death rates, a variety of smoking cessation programs have been employed to help smokers stop smoking. Initially, such programs consisted primarily of behavior modification strategies. Subsequently, nicotine replacement therapy (NRT) was developed in the form of nicotine-containing gum and transdermal patches for use as aids during smoking cessation. Later still, the antidepressant, bupropion was approved for smoking cessation therapy, and was marketed under the trademark ZYBAN(copyright). Over the past decade several programs have been offered which combine behavioral and pharmacological therapies.
Smoking a cigarette causes a rapid but short-lived rise in plasma nicotine. Presumably, the trigger to smoke again occurs as one""s nicotine level falls sufficiently to produce a xe2x80x9ccravingxe2x80x9d sensation. Thus, the height and duration of the nicotine xe2x80x9cspikexe2x80x9d has a major impact on smoking frequency, as well as other behaviors such as puff depth and duration, and nicotine content of the preferred brand of cigarette.
Several lines of evidence suggest that smoking behavior by individual smokers is adapted to produce a pharmacologically relevant concentration of nicotine in the brain and that this level is fairly uniform across individuals, regardless of whether they metabolize nicotine quickly or slowly. Thus smokers with a rapid rate of nicotine metabolism are likely to increase their nicotine intake by smoking frequently, smoking brands high in nicotine, and taking deeper, longer inhalations. Conversely, slow nicotine metabolizers would be expected to exhibit smoking behavior that limits nicotine intake. This has been demonstrated in a recent study where smokers genetically deficient in cytochrome 2A6 were found to smoke less than individuals with normal levels of enzyme activity. See, Pianezza M. L. et al., Genetically Variable CYP2A6 Influences Smoking Behavior, in American Society for Clinical Pharmacology and Therapeutics 63, 171 (1998).
A technical problem of known smoking cessation programs is that they are designed to be xe2x80x9cone size fits allxe2x80x9d. Conventional programs do not provide for individual preferences or biological variations, although the need for individualization of treatment as been realized for some time and has been shown to enhance treatment efficacy. Recent studies have more precisely identified the biological differences among individual smokers suggesting the means for developing and designing improved therapies for treating nicotine addiction.
The individual variation in nicotine metabolism and intake by smokers has important implications in applying smoking cessation strategies. For example, NRT is often used at a single standard dose, which for some individuals may be inappropriate and lead to treatment failure. In the case of slow nicotine metabolizers, a standard dose may be too high, leading to undesirable side effects and to therapeutic failure by maintaining a plasma nicotine level above that which was present during smoking. In contrast, rapid nicotine metabolizers may fail on standard NRT doses because plasma nicotine levels are too low to control cravings.
Although bupropion, as an alternative to NRT, is not metabolized by the same route as nicotine, and thus could serve as an alternative to NRT, bupropion does have contraindications that may preclude its use in all individuals attempting to quit smoking. Thus, a simple inexpensive means of estimating individual rates of nicotine metabolism and intake would be of invaluable assistance to the therapist in assigning a pharmacological intervention with the greatest probability of success.
Cotinine is the metabolic product formed by the action of cytochrome 2A6 on nicotine. Unlike nicotine, which exhibits a biphasic elimination with relatively short half-lives of approximately 10 minutes and 2 hours, cotinine has a long half-life of approximately 19 hours. Thus, cotinine plasma levels are relatively stable and reflect the extent of nicotine conversion by 2A6. Because of its pharmacokinetic properties, cotinine has been widely used to determine the presence of nicotine intake. In pharmacokinetic studies, plasma levels of cotinine in smokers have been shown to be strongly correlated with nicotine dose. Because of cotinine""s relatively long half-life, the timing of the cotinine sampling with respect to smoking activity is not critical.
It is an object of the present invention to solve the technical problem left unaddressed by the prior art, and to provide a method for determining biological variations among individuals in a smoking cessation program so that a therapy regimen can be adjusted appropriately for each individual.
In accordance with this and other objects evident from the following description of a preferred embodiment of the invention, a method of estimating the rate of nicotine metabolism in an individual includes the steps of having the individual intake a predetermined dose of nicotine, taking a saliva sample from the individual at a predetermined time subsequent to intake of the nicotine, and measuring both the nicotine and cotinine levels in the sample. Thereafter, a ratio including the nicotine and cotinine levels is calculated as an indicator of the rate of nicotine metabolism of the individual, and can be used to make adjustments to the individual""s smoking cessation therapy regimen.
By providing a construction in accordance with the present invention, numerous advantages are realized. For example, although evidence exists that plasma cotinine levels reflect nicotine intake, the ratio of plasma nicotine to plasma cotinine concentrations provides a more sensitive measure of estimating nicotine intake or smoking behavior. The reason for this is that plasma nicotine and cotinine concentrations move in opposing directions depending on individual rates of nicotine metabolism. An individual with a rapid rate of nicotine metabolism will smoke more to maintain a pharmacologically active level of nicotine such that their steady state levels of cotinine will be high. After smoking, their levels of nicotine will be lower than normal. Conversely, a slow nicotine metabolizer screened shortly after smoking would present low levels of cotinine and relatively high levels of nicotine compared to the individual who is a rapid nicotine metabolizer.
Thus, a ratio of plasma cotinine/nicotine concentrations obtained soon after smoking provides an estimate of an individual""s metabolic rate for nicotine with an accuracy sufficient to assign an appropriate pharmacological intervention to assist in smoking cessation.